Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art to the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Coronary heart disease (CHD) caused by atherosclerosis, the narrowing of the coronary arteries due to fatty build up of plaque, remains a major healthcare problem in the US. Each year about 450,000 Americans die of CHD, and approximately 1.26 million Americans have a new or recurrent coronary event. CHD is the leading cause of death in the United States [Cardiovascular disease statistics www.americanheart.org/]. In clinical practice, a coronary artery stent, a small mesh tube made of metal or alloys, functions as a scaffold to prop open blocked arteries in the heart to keep them from re-narrowing (referred to clinically as restenosis). However, about 25% of implanted bare metal stents (BMS) still experience restenosis (typically at six-months). In contrast, drug-eluting stents (DES) have reduced the rate of restenosis to <10%, when used for clinically approved indications.
However, concerns were raised in recent years about the safety of DES due to a reportedly small but significantly increased risk of blood clots in the stent within 1 year after stenting (i.e. stent thrombosis). In fact, after DES implantation, late stent thrombosis (i.e. defined as occurring 1-12 months after percutaneous coronary intervention, PCI) occurs in 0.5% of patients, and the risk of very late stent thrombosis (i.e. occurring >1 year after PCI) remains elevated for at least 4 years post stenting [Daemen J, et al.: Lancet. 369: 667-678, 2007]. While not frequent, late stent thrombosis is a life-threatening problem. Delayed healing is considered a leading cause of late stent thrombosis, which has been confirmed by intravascular ultrasound [Alfonso et al. J Am Coll Cardiol. 50: 2095-2097, 2007] and angioscopic studies [Kotani et al. J Am Coll Cardiol. 47: 2108-2111, 2006]. Each year about 600,000 Americans are getting DES [Stent facts. http://americanheart.mediaroom.com/], which means that even a small increased risk could result in thousands of heart attacks and deaths. Furthermore, the requirement for prolonged, aggressive anti-thrombotic therapy after placement of a DES (usually aspirin and clopidogrel) can introduce major complications into the management of patients who require surgical procedures (which necessitate temporary discontinuation of anti-thrombotic drugs) within the first year after PCI.
When compared to coronary bypass graft surgery for restoring blood flow, coronary angioplasty, where inflation of a small balloon in the blocked artery restores blood flow, is a less expensive clinical procedure. Every year about 1.31 million angioplasties through PCI are performed in the US [Angioplasty and Cardiac Revascularization Statistics. www.americanheart.org/]. Restenosis following angioplasty, however, is a major clinical problem since the biological response to this vessel damage is stimulation of accelerated growth of arterial smooth muscle cells. The use of BMS to reduce restenosis rate after angioplasty has revolutionized the field of interventional cardiology [Indolfi et al. Ital Heart J, 6(6): 498-506, 2005]. DES while allowing controlled release of a drug directly to the injured artery for decreased restenosis, have caused late stent thrombosis, which is thought to be attributed to the continuous elution of drugs, leaving a layer of polymer on the surface of stents. The polymer coating may trigger chronic inflammation and hypersensitivity reactions in some patients [Pendyala et al. J Interv Cardio, 22(1): 37-48, 2009]. Autopsy studies indicated that the lack of complete endothelial coverage of stent struts associated with persistence of fibrin deposits, is the primary pathoanatomic substrate of late stent thrombosis after DES implantation [Joner et al. J Am Coll Cardiol. 48: 193-202, 2006; Byrne et al. Minerva Cardioangiol, 57(5): 567-584, 2009]. This delayed healing was not found in patients with BMS.
Therefore, there is a need for coatings and surfaces of medical devices that prevent restenosis and thrombosis, particularly for coronary artery stents for improved safety and efficacy with their use in patients with coronary heart disease.
A variety of methods have been developed for improved biocompatibility of implanted stents. A new drug delivery technology, using a porous stent surface [Tsujino et al. Expert Opin Drug Deliv, 4(3): 287-295, 2007], may offer desirable drug elution properties. However, it is still at an early stage. Biodegradable polymers are being explored as a new platform for DES [Grube et al. Expert Rev Med Devices, 3(6): 731-741, 2006; Lockwood et al. Biomater Sci Polym Ed, 21(4): 529-552, 2010], but further investigation for clinical use is needed, and recent morphology studies of biodegradable coatings have shown cracks in the coatings after stent expansion [Basalus et al. EuroIntervention. 5(4): 505-10, 2009]. The performance and efficacy of the polymer-free vestasync-eluting stent (VES) have been investigated recently [Costa et al. JACC Cardiovasc Interv. 1(5): 545-551, 2008], but a long term follow-up with a more complex subset of patients and lesions is required to confirm their preliminary results. A novel polymer coating adsorbed to stent surfaces was revealed to reduce neointimal hyperplasia in a 6 week porcine restenosis model [Billinger et al. J Invasive Cardiol, 18(9): 423-427, 2006], but whether or not it will develop late thrombosis in stent is an unanswered question. Polyurethane coating has been applied to stents and found to inhibit platelet attachment [Fontaine et al. J Vasc Interv Radiol, 5: 567-572, 1994; Fontaine et al. J Endovasc Sur, 3: 276-283, 1996] and reduce thrombogenicity [Tepe et al. Biomaterials, 27(4): 643-650, 2006]. However, long-term implantation of polyurethane-coated stents has also been found to induce chronic inflammation [van de Giessen et al. Circulation, 94: 1690-1697, 1996]. A new dual acting polymeric coating that combines NO (nitric oxide) release with surface-bound heparin was developed to prevent thrombosis to mimic the nonthrombogenic properties of the endothelial cell layer that lines the inner wall of healthy blood vessels [Zhou et al. Biomaterials, 26: 6506-6517, 2005]. However, no systematical study for stent application has been reported. Another approach is to attach radioactive material to the stent surface to prevent restenosis [Zamora et al. J Biomed Mater Res (Appl Biomater), 53: 244-251, 2000], but the polyurethane used as a sealant for the radioactive agent on the stent surface remains problematic in causing chronic inflammation. A new biomimetic nanostructured coating (no drugs) on titanium was reported to significantly increase endothelial cell density, but further exploration is needed for stent application [Fine et al. Int J Nanomedicine. 4:91-97, 2009]. In summary, none of those aforementioned approaches addresses both issues of late thrombosis and in-stent restenosis with one specific coating. It has been noted that Orbus Neich promotes its coating to both prevent thrombosis and lower the risk of restenosis. The coating process consists of three steps including a surface priming process, bio-chemical reaction, and covalent bonding [Orbus Neich Expands Global Sales and Marketing Team. www.orbusneich.com/genous/]. The use of two drugs coated on stents to simultaneously minimize both restenosis and thrombosis has been studied recently [Huang et al. J Interv Cardiol, 22 (5): 466-478, 2009]. The animal studies showed a significant reduction in restenosis, but whether or not the late stent thrombosis will develop remains unclear.
In recent years, plasma processes have been widely used in the preparation of biomedical materials with unique performance and in the manufacturing of medical devices [Ratner BD in: Plasma Processing of Polymers, 1997]. For instance, a new nitrogen-rich plasma-deposited biomaterial as an external coating for stent-grafts can promote healing around the implant after endovascular aneurysm repair [Lerouge et al. Biomaterials, 28(6):1209-1217, 2007]. Plasma deposition is a thin film forming process typically occurring in a vacuum chamber, where thin films deposit on the surface of substrates under plasma conditions. In a plasma deposition process, monomers are introduced into a plasma reactor and get activated to produce a gaseous complex composed of highly energetic electrons, ions, free radicals and excited monomer molecules, known as the plasma state. Through plasma deposition, many appropriate functional groups, such as amine, hydroxyl, carboxylic acid, useful for the immobilization of bioactive molecules, can be created in the deposited coatings. More importantly, these chemical groups can be put onto almost any material by choosing right monomers and plasma process parameters.
Plasma surface treatment has also become a powerful tool in solving surface preparation problems on biomedical materials [Chu et al. Mater Sci Eng, R36: 143-206, 2002]. Oxygen plasmas, for example, have been used to increase the attachment of cells to polymer surfaces [Ertel et al. J Biomater Sci Polym Ed, 3:163-183, 1991; Chilkoti et al. Anal Chem, 67: 2883-2891, 1995; Ertel et al. J Biomed Mater Res, 24: 1637-1659, 1990]. Plasmas have also been used to introduce amines and amides to polymeric materials for increasing the attachment of cells, and in particular endothelial cells [Griesser et al. J Biomater Sci Polym Ed, 5: 531-554, 1994; Ramires et al. J Biomed Mater Res, 51: 535-539, 2000; Tseng et al. J Biomed Mater Res, 42: 188-198, 1998; Harsch et al. J Neurosci Methods, 98: 135-144, 2000]. Absorption of two blood proteins, fibronectin and vitronectin, is also modified by plasma treatment [Mooradian et al. J Surg Res, 53: 74-81, 1992; Steele et al. J Biomater Sci Polym Ed, 6: 511-532, 1994], and that directly influences endothelial cell attachment. In addition to polymers, surfaces of metals like stainless steel and titanium, which are widely used in the construction of medical devices [Gotman J Endourol, 11: 383-389, 1997], have also been treated with plasmas for a variety of purposes.
U.S. Pat. No. 6,613,432, provides a method of using plasma surface modification to introduce a bioactive layer or coating on the surface of implantable medical devices for improved biocompatibility, such as inhibition of restenosis with stents and attachment of platelets and leukocytes. However, in large animal studies with this patented plasma technology, certain, often large variations have been observed on the patency of plasma treated stents after implantation, which is believed to be due to the potential instability of surface bioactivity generated by the single-step NH3/O2 plasma surface treatment on bare stainless steel surfaces.
As discussed above, the currently available coronary stents and the methods under development for improved biocompatibility of stents have the following crucial problems: 1) existing stent procedures with BMS still experience a high incidence of restenosis; 2) although DES, in comparison with BMS, have been much more widely used due to their better ability in controlling restenosis carry the risk of developing late stent thrombosis, which is associated with a clinically significant risk of mortality; and 3) most existing coating processes investigated have the major limitation of being incapable of preventing restenosis and thrombosis at the same time. Thus it would be desirable to provide new coatings for surfaces of medical devices that exhibit both reduced restenosis and thrombosis. In particular, it would be desirable to provide methods for preparing and fabricating devices and substrates to prevent these problems from happening.